Genetic Variant ENST00000481487.1:n.1267C>T (chr1-32862564-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000481487.1(FNDC5):n.1267C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 152,504 control chromosomes in the GnomAD database, including 24,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24479 hom., cov: 32)

Exomes 𝑓: 0.59 ( 80 hom. )

Consequence

FNDC5
ENST00000481487.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.722

Publications

52 publications found

Variant links:

Genes affected

FNDC5 (HGNC:20240): (fibronectin type III domain containing 5) This gene encodes a secreted protein that is released from muscle cells during exercise. The encoded protein may participate in the development of brown fat. Translation of the precursor protein initiates at a non-AUG start codon at a position that is conserved as an AUG start codon in other organisms. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

FNDC5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 1-32862564-G-A is Benign according to our data. Variant chr1-32862564-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FNDC5	NM_153756.3 link	c.*1730C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000373471.9	NP_715637.2	Q8NAU1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FNDC5	ENST00000373471.9 link	c.*1730C>T		3_prime_UTR_variant	Exon 6 of 6	2	NM_153756.3	ENSP00000362570.5		Q8NAU1-1A0A0A0MRR6

Frequencies

GnomAD3 genomes

AF:

0.565

AC:

85898

AN:

151906

Hom.:

24488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.681

Gnomad AMR

AF:

0.592

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.741

Gnomad SAS

AF:

0.568

Gnomad FIN

AF:

0.559

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.594

Gnomad OTH

AF:

0.590

GnomAD4 exome

AF:

0.588

AC:

282

AN:

480

Hom.:

Cov.:

AF XY:

0.577

AC XY:

172

AN XY:

298

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.582

AC:

248

AN:

426

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.639

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.565

AC:

85914

AN:

152024

Hom.:

24479

Cov.:

AF XY:

0.562

AC XY:

41785

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.489

AC:

20270

AN:

41460

American (AMR)

AF:

0.592

AC:

9042

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1750

AN:

3466

East Asian (EAS)

AF:

0.741

AC:

3820

AN:

5158

South Asian (SAS)

AF:

0.567

AC:

2724

AN:

4808

European-Finnish (FIN)

AF:

0.559

AC:

5907

AN:

10568

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.594

AC:

40364

AN:

67966

Other (OTH)

AF:

0.593

AC:

1253

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1914

3828

5741

7655

9569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

734

1468

2202

2936

3670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.586

Hom.:

38295

Bravo

AF:

0.567

Asia WGS

AF:

0.680

AC:

2361

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 24, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30389552) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.72

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over